State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China.
Nat Commun. 2020 Mar 20;11(1):1507. doi: 10.1038/s41467-020-15112-3.
Tumor cells often reprogram their metabolism for rapid proliferation. The roles of long noncoding RNAs (lncRNAs) in metabolism remodeling and the underlying mechanisms remain elusive. Through screening, we found that the lncRNA Actin Gamma 1 Pseudogene (AGPG) is required for increased glycolysis activity and cell proliferation in esophageal squamous cell carcinoma (ESCC). Mechanistically, AGPG binds to and stabilizes 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3). By preventing APC/C-mediated ubiquitination, AGPG protects PFKFB3 from proteasomal degradation, leading to the accumulation of PFKFB3 in cancer cells, which subsequently activates glycolytic flux and promotes cell cycle progression. AGPG is also a transcriptional target of p53; loss or mutation of TP53 triggers the marked upregulation of AGPG. Notably, inhibiting AGPG dramatically impaired tumor growth in patient-derived xenograft (PDX) models. Clinically, AGPG is highly expressed in many cancers, and high AGPG expression levels are correlated with poor prognosis, suggesting that AGPG is a potential biomarker and cancer therapeutic target.
肿瘤细胞经常重新编程其代谢以快速增殖。长链非编码 RNA（lncRNA）在代谢重塑中的作用及其潜在机制仍不清楚。通过筛选，我们发现肌动蛋白γ 1 假基因（AGPG）对于食管鳞状细胞癌（ESCC）中糖酵解活性和细胞增殖的增加是必需的。在机制上，AGPG 结合并稳定 6-磷酸果糖-2-激酶/果糖-2,6-二磷酸酶 3（PFKFB3）。通过防止 APC/C 介导的泛素化，AGPG 保护 PFKFB3 免受蛋白酶体降解，导致 PFKFB3 在癌细胞中的积累，从而激活糖酵解通量并促进细胞周期进程。AGPG 也是 p53 的转录靶标；TP53 的缺失或突变会触发 AGPG 的显著上调。值得注意的是，抑制 AGPG 可显著抑制患者来源的异种移植（PDX）模型中的肿瘤生长。临床上，AGPG 在许多癌症中高表达，并且高 AGPG 表达水平与预后不良相关，表明 AGPG 是一种潜在的生物标志物和癌症治疗靶标。
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